CRYPTOVACC

Development of fungal conjugate vaccines based on synthetic oligosaccharide structures

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 Obiettivo del progetto (Objective)

'Attempts to prepare conjugate vaccines based on native capsular polysaccharide structures against Cryptococcus neoformans, a fungi increasingly recognized as a major health issue, has been ineffective due to the heterogeneity of the native material. In this project well defined synthetic oligosaccharide structures will be used instead. A library of structures corresponding to native structures will be synthesized and utilized in the production of glycomicroarrays. These will be employed to screen monoclonal antibodies raised against the native polysaccharide to determine their specificity and to identify protective carbohydrate epitopes. Recognized hits will be conjugated to carrier proteins using various spacers and conjugation techniques to produce a selection of vaccine candidates which efficiency will be evaluated in immunizing experiments in mice by collaborators. The training will be multidisciplinary covering complex oligosaccharide synthesis, conjugation techniques, microarray construction, protein and antibody purification and labelling, macromolecular characterisation and biological screening methods. The project is an international collaboration between chemists, immunologists and vaccine industry.'

Introduzione (Teaser)

A vaccine against fungal infections is long overdue and should significantly benefit individuals with an enhanced susceptibility to infection.

Descrizione progetto (Article)

Cryptococcus neoformans is an opportunistic yeast that causes cryptococcal meningoencephalitis (cryptococcosis) in immunocompromised individuals. Attempts so far to generate vaccines have produced mixed results. This is due to the heterogeneity of the capsular polysaccharide (CPS) in the fungus which generates both protective and non-protective antibodies.

Glycoconjugate vaccines are generally considered safe and efficient comprising the majority of the vaccine market. However, at the moment there are no commercial glycoconjugate vaccines against fungal infections. To address this, researchers of the EU-funded CRYPTOVACC (Development of fungal conjugate vaccines based on synthetic oligosaccharide structures) project proposed to generate the first vaccine against C. neoformans using a synthetic CPS as an immunogen.

For this purpose, researchers employed a wide range of techniques including oligosaccharide synthesis, microarray construction, protein and antibody purification and labelling as well as biological screening methods.

The first step was to implement high-yielding and reproducible procedures to synthesise structures of the CPS of Cryptococcus neoformans. In this context CRYPTOVACC devised a multi-step method to generate well-defined polysaccharide blocks. They removed any permanent protecting groups to make compounds suitable for microarray printing.

An array of CPS synthetic structures was printed on activated glass microarray plates and screened with a library of monoclonal antibodies raised against the native polysaccharide. This was performed to identify protective epitopes that could be later utilised for vaccination.

Taken together, the results of the project represent a fundamental advance in the development of a synthetic glycoconjugate vaccine against C. neoformans.